Analgesic and Respiratory Depressant Effects of R-dihydroetorphine

Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. Methods The authors performed a population pharmacokinetic–pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. Results R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. Conclusions Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Oral Oxycodone‐Induced Respiratory Depression During Normocapnia and Hypercapnia: A Pharmacokinetic‐Pharmacodynamic Modeling Study

“…When comparing utilities among μ‐opioids (considering similarities in outcomes and study populations), the performance of oxycodone was superior to that of fentanyl but inferior to that of two other, unfamiliar μ‐opioids, cebranopadol and R‐dihydroetorphine 2,3,5 . In all of these studies, isohypercapnic ventilation and electrical pain were used as input to the utility functions.…”

“…R-dihydroetorphine is full agonist with high for μ-, κ-, and δopioid receptors and low affinity for the nociceptin receptor. 5 Its positive utility function may be related to the respiratory protective effect exerted by κand δopioid receptor activation. 22,23 The full μopioid receptor agonist cebranopadol has a positive utility that may be related to its agonistic activity at the nociception-receptor, counteracting part of the respiratory depression from the μopioid agonism.…”

“…PK/PD studies that consider both end points will give an indication of the opioid utility in the treatment of pain. [2][3][4][5][6][7] It enables optimizing the dose that is associated with the likelihood of high efficacy and low toxicity. Additionally, such analyses will allow comparison among opioids and may help in the selection of specific opioids for treatment of pain, rather than relying on intuition and/or trial-and-error when choosing an opioid.…”

Pharmacologically Induced Ventilatory Depression in the Postoperative Patient: A Sleep-Wake State-Dependent Perspective

“…When feasible, the use of regional rather than general anesthesia, as well as the careful intraoperative titration of the latter, may allow, to some extent, more rapid recovery of stable wakefulness. Moreover, decreasing the analgesic need for opioids, and exploring the use of opioids with a better profile for ventilatory depressants effects, 149,150 or developing novel ventilatory-specific opioid reversal agents, 151 could also be of fundamental importance in an effort to reduce the incidence of postoperative PIVD. 152 Re-establishment of wakefulness drive to breath could facilitate maintenance of the UA by increasing ventilatory drive and motor output to pharyngeal dilator muscles.…”

NMR Analysis of a Series of 6,14‐Ethenomorphinan Derivatives as PET Precursors and Reference Substances**

“…[28] Nonetheless, DHE is an approved drug in China for medication of severe/acute pain. DHE is a full agonist with high or moderate affinity for all OR subtypes ([K i (μ) = 0.1 nM, K i (δ) = 1.5 nM, K i (k) = 0.74 nM, K i (NOP) = 120 nM] [29] and [K i (μ) = 0.5 nM, K i (δ) = 3.8 nM, K i (k) = 0.3 nM [towards human cloned opioid receptors] [30] ).…”